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Laboratory for Molecular Pharmacology, University Department of
Clinical Pharmacology, Rigshospitalet, DK-2100, Copenhagen, Denmark
(S.P., C.M.C.-M., A.A.M., H.T.S., S.A.H., T.W.S.),
Department of
Exploratory Chemistry, Merck Research Laboratories, Rahway, New Jersey
07065 (R.A.R., W.J.G.),
Department of Biophysics, Escola Paulista de
Medicina, UNIFESP, S Two nonpeptide ligands that differ chemically by only a single methyl
group but have agonistic (L-162,782) and antagonistic (L-162,389)
properties in vivo were characterized on the cloned angiotensin AT1 receptor. Both compounds bound with high
affinity (KI = 8 and 28 nM, respectively) to the AT1 receptor expressed transiently in COS-7 cells as determined in radioligand competition assays. L-162,782 acted as a powerful partial agonist, stimulating phosphatidylinositol turnover with a bell-shaped
dose-response curve to 64% of the maximal level reached in response to
angiotensin II. Surprisingly, L-162,389 also stimulated
phosphatidylinositol turnover, albeit only to a small percentage of the
angiotensin response. The prototype nonpeptide AT1 agonist
L-162,313 gave a response of ~50%. The apparent EC50
values for all three compounds in stimulating phosphatidylinositol
turnover were similar, ~30 nM, corresponding to
their binding affinity. Each of the three compounds also acted as
angiotensin antagonists, yet in this capacity the compounds differed
markedly, with IC50 values ranging from 1.05 × 10
o Paulo 04023-062, Brazil (C.M.C.-M.,
A.A.M., A.C.M.P.), and
Department of Protein Chemistry, Institute of
Molecular Biology, University of Copenhagen, DK-1353, Copenhagen,
Denmark (T.W.S.)
7 M for L-162,389 to 6.5 × 106 for L-162,782. A series of point mutations in the
transmembrane segments (TMs) of the AT1 receptor had only
minor effect on the binding affinity of the nonpeptide compounds, with
the exception of A104V at the top of TM III, which selectively impaired
the binding of L-162,782 and L-162,389. Substitutions in the middle of
TM III, VI, or VII, which did not affect the binding affinity of the
compounds, impaired or eliminated the agonistic efficacy of the
nonpeptides but with only minor or no effect on the angiotensin potency
or efficacy. Thus, in the N295D rat AT1 construct,
L-162,782, L-162,313, and L-162,389 all antagonized the
angiotensin-induced phosphatidylinositol turnover with surprisingly
similar IC50 values (90-180 nM), and they
all bound with unaltered, high affinity (22-36 nM).
However, L-162,313 and L-162,782 could stimulate phosphatidylinositol turnover to only 20% of that of angiotensin. It is concluded that minor chemical modifications of either the compound or the receptor can
dramatically alter the agonistic efficacy of biphenyl imidazole compounds on the AT1 receptor without affecting their
affinity, as determined in binding assays, and that a number of
substitutions in the middle of the TM segments affect the efficacy of
nonpeptide agonists as opposed to angiotensin.
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